The present invention relates to a process for the preparation of ketimines, which are suitable as starting materials for the preparation of pharmaceutical active compounds having antidepressant properties, for example sertraline.
Processes for the preparation of ketimines are described, for example, in U.S. Pat. No. 4,536,518 or U.S. Pat. No. 4,855,600.
The process for the preparation of ketimines disclosed in U.S. Pat No. 4,536,518 (columns 9/10, Example 1(F)) is characterized in that the ketone is reacted with methylamine with cooling in the presence of titanium tetrachloride in an aprotic solvent, for example tetrahydrofuran. This process has the disadvantage that it has to be carried out using titanium tetrachloride, which is ecologically hazardous. The process procedure is additionally expensive, because the reaction is carried out with cooling. A further disadvantage of this process relates to the work-up. The product must be precipitated using additional hexane.
The process for the preparation of ketimines disclosed in U.S. Pat No. 4,855,500 (columns 5/6, claim 1) comprises reacting the ketone with anhydrous methylamine with cooling in an aprotic solvent, such as, for example, methylene chloride, toluene or tetrahydrofuran in the presence of a molecular sieve.
This process has the disadvantage that the molecular sieve employed is expensive and has to be recycled again in an additional step. A further disadvantage of this process is that the molecular sieve has to be separated off and the product precipitated using additional hexane.
There is therefore furthermore the need to find an efficient process for the preparation of ketimines, which does not have the abovementioned disadvantages.
The present invention therefore relates to a process for the preparation of compounds of the formula 
in which
R1, R2 and R3 independently of one another are hydrogen, halogen, trifluoromethyl or C1-C4alkoxy, wherein a compound of the formula 
in which
R1, R2 and R3 are as defined in formula (1) is reacted with methylamine in the presence of a C1-C24amine or C1-C12nitrile as solvent to give the compound of the formula (1), or
is reacted with methylamine in the presence of a sulfonic acid catalyst and of a non-alcoholic solvent to give the compound of the formula (1).
Halogen is, for example, chlorine, bromine or iodine. Chlorine is preferred.
C1-C4alkoxy is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred.
The non-alcoholic solvent preferred for the process according to the invention is preferably selected from
(a) C1-C24amines,
(b) C1-C12nitriles,
(c) C2-C24carboxylic acid esters,
(d) C3-C24orthoesters,
(e) C2-C24ethers,
(f) C6-C24alkanes,
(g) aromatic solvents,
(h) amides,
(i) sulfoxides,
(k) halogenated solvents, and
(j) supercritical CO2.
Particularly preferred solvents (a) are selected from aliphatic monoamines, in particular methylamine, nitrogen heterocycles, aliphatic di- and triamines, non-substituted or substituted aromatic monoamines or aromatic diamines.
Further preferred solvents (a) are those of the formula 
in which
R3 is hydrogen; C1-C5alkyl; hydroxy-C1-C5alkyl; C5-C7cycloalkyl; phenyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; phenyl-C1-C3alkyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro;
R4 and R5, independently of one another, are C1-C5alkyl; hydroxy-C1-C5alkyl; C5-C7cycloalkyl; phenyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; phenyl-C1-C3alkyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; or
R4 and R5 together with the nitrogen atom form a three- to 6-membered heterocyclic radical.
Furthermore, solvents (a) are preferably used which are those of the formula 
in which
R6 and R8 independently of one another are hydrogen; C1-C5akyl; or C5-C7cycloalkyl, R7 and R9 independently of one another are C1-C5alkyl; or C5-C7cycloalkyl, phenyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; phenyl-C1-C3alkyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; or
R6 and R7, R8 and R9 or R7 and R9 form a three- to 6-membered heterocyclic radical; and A2 is C1-C5alkylene.
Exemplary representatives of solvents (a) used according to the invention which may be mentioned are:
as aliphatic monoamines, for example, methylamine, dimethylamine, triethylamine, diethylamine, triethylamine, di-n-propylamine, diisopropylamine, tri-n-propylamine, or triisopropylamine;
as nitrogen heterocycles ethyleneimine, pyrrolidine, piperidine or morpholine,
as aliphatic diamines, for example, N,N-dimethylethylenediamine or hexamethylenediamine;
as aromatic monoamines, for example, N-methylaniline or N,N-dimethylaniline;
as substituted aromatic monomamines, for example, o-, m- or p-toluidine, 2-, 3- or
4-chloroaniline, 2-, 3- or 4-nitroaniline;
as aromatic diamines, for example, o-, m- or p-phenylenediamine.
Solvents (b) preferably used are those of the formula 
in which
R10 is straight-chain or branched C1-C12alkyl; C5-C7cycloalkyl; phenyl which is not substituted or is substituted by one or more C1-C5akyl groups, halogen or nitro; phenyl-C1-C3alkyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro.
Exemplary representatives of this group are benzonitrile or in particular acetonitrile. Solvents (c) which are preferably used are compounds of the formula 
in which
R12 and R13 independently of one another are straight-chain or branched C1-C12alkyl; C5-C7cycloalkyl; or phenyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; phenyl-C1-C3alkyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro.
Exemplary representatives of these solvents are acetates, such as, for example, methyl acetate or ethyl acetate.
Solvents (d) preferably employed according to the invention are those of the formula 
in which
R14 is hydrogen; straight-chain or branched C1-C5alkyl; or C5-C7cycloalkyl; and
R15 is C1-C5alkyl.
Exemplary representatives of these solvents are C1-C3alkyl orthoformates, in particular methyl or ethyl orthoformate or C1-C3alkly orthoacetates, in particular ethyl orthoacetate. Solvents (e) preferably employed according to the invention are those of the formula
R16xe2x80x94Oxe2x80x94R17, in which (8)
R16 and R17 independently of one another are hydrogen; straight-chain or branched C1-C12alkyl; or C5-C7cycloalkyl; or R16 and R17 together with the oxygen atom form a 5- to 6-membered radical.
Exemplary representatives of those solvents are dimethyl ether, diethyl ether, methyl ethyl ether, methyl n-propyl ether, methyl i-propyl ether, diisopropyl ether, dibutyl ether or tert-butyl methyl ether. In addition, polyethers can also be employed.
Solvents (f) preferably employed according to the invention are saturated C1-C22hydro-carbons, such as, for example, methane, ethane, propane, butane, pentane, hexane, neohexane, heptane, octane, i-octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, eicosane, heneicosane or docosane.
Solvents (g) preferably employed according to the invention are in particular benzene, toluene, xylene and xylene isomer mixtures.
Solvents (h) preferably employed according to the invention are in particular aliphatic and aromatic amides of the formula

in which
R18 and R19 independently of one another are hydrogen; C1-C5alkyl; or C5-C7cycloalkyl, and
R20 is C1-C5alkyl; C5-C7cycloalkyl; phenyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro; or phenyl-C1-C3alkyl which is not substituted or is substituted by one or more C1-C5alkyl groups, halogen or nitro.
Exemplary solvents (i) are those of the formula
R21xe2x80x94(Sxe2x95x90O)xe2x80x94R22, in whichxe2x80x83xe2x80x83(10)
R21, and R22 independently of one another are C1-C5alkyl; C5-C7cyclalkyl; phenyl which is not substituted or which is substituted by one or more C1-C5alkyl groups, halogen or nitro; or phenyl-C1-C3alkyl which is not substituted or which is substituted by one or more C1-C5alkyl groups, halogen or nitro.
Exemplary solvents (k) are those of the formula
ClCR23R24R25,xe2x80x83xe2x80x83(11a)
Cl2CR26R27 orxe2x80x83xe2x80x83(11b)
Cl3-CR28,in whichxe2x80x83xe2x80x83(11c)
R23, R24, R25, R26, R27 and R28 independently of one another are C1-C5alkyl; C5-C7cycloalkyl; phenyl which is not substituted or which is substituted by one or more C1-C5alkyl groups, halogen or nitro; or phenyl-C1-C3alkyl which is not substituted or which is substituted by one or more C1-C5alkyl groups, halogen or nitro.
Exemplary representatives of this solvent class are dichloroethane, dichloropropane, trichloroethane, furthermore haloaromatics, for example chlorobenzene or dichlorobenzene.
If supercritical CO2 is used, the reaction is carried out at temperatures Txe2x89xa7Tcrit and pxe2x89xa7pcrit in CO2 as solvent. After the reaction, CO2 is evaporated and the imine is discharged as solid.
The solvents employed according to the invention can be used as individual compounds or as mixtures of two or more individual compounds of identical or different solvent groups a)-(l).
In addition, there is the possibility of adding further solubilizing or solubility-inhibitng additives (e.g. toluene or cyclohexane)
If the preparation of the compound of the formula (1) is carried out with methylamine in the presence of a C1-C24 amine or C1-C12nitrile as solvent (with or without catalyst), the conditions and preferences indicated above for the solvent (a) apply for the C1-C24amines and those indicated above for the solvent (b) apply for the C1-C12nitriles. The use of solvents (b) is preferred here.
Generally, the use of solvents (a) or (b), in particular (b), is preferred.
Suitable sulfonic acid catalysts are, for example, methanesulfonic acid, p-toluenesulfonic acid or camphor-10-sulfonic acid.
A process for the preparation of compounds of the formula (1) is especially preferred in which a sulfonic acid catalyst is used, in particular p-toluenesulfonic acid, methanesulfonic acid or camphor-10-sulfonic acid.
The molar quantitative ratio of the catalyst employed to the methylamine employed is expediently 0.001:1 to 1:1, in particular 0.01:1 to 0.5:1, e.g. 0.05:1 to 0.1:1.
The 1:1 molar quantitative ratio of the catalyst to the methylamine also means that the methylamine can also be employed in the process according to the invention in the form of a salt, for example of methylamine hydrochloride.
The process according to the invention is preferably carried out at a temperature from 20 to 120, in particular 30 to 100xc2x0 C., if appropriate under slight pressure, and the isolation at a temperature from xe2x88x9220 to 40, in particular 0 to 30xc2x0 C.
For the preparation of the compound of the formula (1) in the presence of a catalyst, a temperature range from 30 to 80xc2x0 C., in particular 30 to 70xc2x0 C. and preferably 30 to 60xc2x0 C., is preferred.
For the preparation of the compound of the formula (1) without the presence of a catalyst, a temperature range from 50 to 120xc2x0 C., in particular 70 to 120xc2x0 C. and preferably 80 to 120xc2x0 C., is preferred. The upper value of the temperature range preferred here is 110xc2x0 C., in particular 100xc2x0 C.
The proportion of sertralone in the reaction mixture is, for example, in the range from 5 to 70, preferably 30 to 60, % by weight.
The reaction is particularly preferably carried out using a large molar excess of methylamine.
A process for the preparation of compounds of the formula (1) is therefore particularly preferred in which the molar quantitative ratio of the compound of the formula (2) to methylamine is 1:1 to 1:1000, in particular 1:1.05 to 1:50, e.g. 1:1.5 to 1:15.
The methylamine can be employed in the form of methylamine gas or as a solution in a non-alcoholic solvent.
A process variant is of very particular interest in which the reaction can be carried out in pure methylamine, in particular under pressure, this compound being employed simultaneously as a solvent and reagent. In this case, customarily no significant amounts of further solvent are employed.
Also of particular interest is a process for the preparation of compounds of the formula (1) in which the compound of the formula (1) is continuously crystallized from the reaction medium during the preparation and then filtered off.
Also of especial interest is a process for the preparation of compounds of the formula (1), in which the filtrate is employed for a further reaction for the preparation of compounds of the formula (1). In this case, the amounts of the compound of the formula (2) and methylamine used are replenished. 2 to 10 recyclings of the filtrate are preferred.
The present process according to the invention is accordingly also suitable as a continuous process for the preparation of the compounds of the formula (1).
The water formed during the process can be bound, if desired, using an additional chemical water-binding agent for example an orthoester, e.g. trimethyl orthoformate.
After reaction is complete, if desired, the compound of the formula (1) obtained can be subjected to purification by recrystallization.
Preferably, for this purification process a solvent is employed which is selected from
(a) C1-C24amines,
(b) C1-C12nitriles,
(c) C2-C24carboxylic acid esters,
(d) C3-C24orthoesters,
(e) C2-C24ethers,
(f) C6-C24alkanes,
(g) aromatic solvents,
(h) amides,
(i) sulfoxides,
(k) halogenated solvents,
(l) supercritical CO2,
(m) protic solvents, and
(n) C2-C24ketones.
The solvents (a) to (l) are the solvents which are also used for the reaction.
The protic solvent (m) is preferably an alcohol, which in particular is of the formula
xe2x80x83X(OH)bxe2x80x83xe2x80x83(12)
in which
b is 1, 2, 3 or 4, and
if b is 1,
X is C1-C8alkyl, C5-C8cycloalkyl or xe2x80x94CH2CH2(OCH2CH2)cR21,
0, 1 or 2, and
R2, is C1-C4alkoxy, or
if b is 2,
X is C2-C8alkylene or xe2x80x94CH2CH2(OCH2CH2)cxe2x80x94, where c has the above meaning, or
if b is 3,
X is C3-C8alkanetriyl or N(CH2CH2)3, or
if b is 4,
X is C4-C8alkanetetrayl.
In the abovementioned definitions of the radicals R1 to R21:
C1-C12alkyl is a branched or unbranched hydrocarbon radical, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3 tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, isooctyl, nonyl, decyl, undecyl or dodecyl.
C5-C8cycloalkyl is, for example, cyclopentyl, cycloheptyl, cyclooctyl or preferably cyclohexyl.
C1-C4alkoxy is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred.
C2-C12alkenyl is, for example, allyl, methallyl, isopropenyl, 2-butenyl, 3butenyl, isobutenyl, n-penta-2,4-dienyl, 3-methylbut-2enyl, n-oct-2-enyl, n-dodec-2-enyl, isododecenyl, n-dodec-2-enyl or n-octadec-4-enyl.
C3-C12alkynyl is C3-C12alkyl or C3-C12alkenyl, which is mono- or polydiunsaturated, where the triple bonds can, if desired, be isolated or conjugated with one another or with double bonds, for example 1-propyn-3-yl, 1-butyn-4-yl, 1-pentyn-5-yl, 2-methyl-3-butyn-2-yl, 1,4-pentadiyn-3-yl, 1,3-pentadiyn-5-yl, 1-hexyn-6-yl, cis-3-methyl-2-penten-4-yn-1-yl, trans-3-methyl-2-pentyn-4-yn-1 -yl, 1,3-hexadiyn-5-yl, 1-octy-8-yl, 1-nonyn-9-yl or 1-decyn-10-yl.
C2-C8alkylene is a branched or unbranched radical, for example ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or octamethylene.
Alkanetriyl having 3 to 8 carbon atoms is derived, for example, from an alkane having 3 to 8 carbon atoms, in which 3 hydrogen atoms are absent and is, for example 
Glyceryl is preferred.
Alkanetetrayl having 4 to 8 carbon atoms is derived, for example, from an alkane having 4 to 8 carbon atoms, in which 4 hydrogen atoms are absent, and is, for example 
Pentaerythrityl is preferred.
A preferred meaning of X (for b=1) is, for example, C1-C6alkyl, in particular C1-C4alkyl, e.g. ethyl or isopropyl.
A preferred meaning of X (for b=2) is, for example, C2-C6alkylene, in particular C2-C4alkylene, e.g. ethylene.
Of particular interest is a process for the preparation of compounds of the formula (1), in which the protic solvent is a compound of the formula (12), in which
b is 1 or 2, and
if b is 1,
X is C1-C4alkyl or C5-C6cycloalkyl, or
if b is2,
X is C2-C4alkylene.
Practically relevant alcohols for the purification step are methanol, ethanol, isopropanol, n-butanol, ethylene glycol, methylcellosolve, cyclohexanol, diethylene glycol or triethanolamine.
Solvents employed for the purification process are furthermore C2-C24ketones (=Component (n)), which in particular are those of the formula 
in which
R22 and R23 independently of one another are branched or unbranched C1-C12alkyl; C5-C7cycloalkyl; C2-C12alkenyl; C3-C12alkynyl; phenyl or phenyl-C1-C3alkyl, which is not substituted or is substituted by one or more C1-C5alkyl groups;
A1 is a direct bond; or C1-C5alkylene; and n is 0 or 1.
Exemplary representatives of this group are, for example, aliphatically saturated ketones, such as, for example, propanone (acetone), butanone (methyl ethyl ketone) or 2-pentanone (methyl propyl ketone); cycloaliphatically saturated ketones, for example cyclopentanone, cyclohexanone or cycloheptanone (suberone); aliphatically unsaturated ketones, for example 3buten-2-one, 1,4-pentadien-3-one, 3-pentyn-2-one; aromatic ketones, for example benzophenone; aromatic/aliphatic ketones, for example methyl phenyl ketone (acetophenone) or propiophenone; diketones, for example 2,3-butanedione, 2,4-pentanedione or 2,5-hexanedione; or aromatic diketones, for example diphenylethanedione (benzil).
In a particularly preferred embodiment, the purification is carried out in the same solvent as the reaction.
In a preferred process variant, the purification is carried out by recrystallization of sertraline (compound of the formula (1)) under reflux. For this, the isomerically pure sertraline is introduced in a suitable solvent into a suitable reaction vessel having a stirrer and reflux condenser. The reaction mass is heated to reflux temperature in an inert gas atmosphere with stirring until a clear solution is present. The solution is cooled to the appropriate isolation temperature, the product slowly crystallizing. The suspension is filtered, and the filter cake is washed with the solvent and dried. The imine yield is from 80 to 99%, with a sertralone content of 0.1 to 5.0% (HPLC), a catalyst contamination ofxe2x89xa60.01 and up to 0.3% water content.
In a further process variant, the recrystallization of sertraline is carried out under pressure. For this, the crude sertraline and the solvent are introduced into a suitable pressure reactor having a stirrer. The reactor is sealed under a nitrogen atmosphere. The stirrer is started and the reaction mixture is heated to the desired reaction temperature until a clear solution is present. The solution is cooled to the appropriate isolation temperature, the product slowly precipitating. The suspension is filtered, and the filter cake is washed with the solvent and dried.
The solution temperatures in the selected solvents are in the range from 30 to 150, preferably 70 to 120xc2x0 C.
According to the boiling points of the solvents indicated, the purification process can be carried out at normal pressure under reflux or at elevated pressure, normally in the range from 0 to 10, preferably from 0 to 3, bar.
The cooling gradients are in the range from 0.05 to 10, preferably 0.1 to 1, xc2x0 C./min.
The isolation temperatures are in the range from xe2x88x9220 to 40, preferably 0 to 25, xc2x0 C.
The concentrations of crude sertraline in the clear solution are in the range from 5 to 40, preferably 15 to 20, % by weight.
During the process, adsorbents, for example active carbon or adsorber resins, can be added for the removal of colouring impurities. These adsorbents are added to the clear solution in amounts from 1 to 10% and removed hot by filtration before the crystallization process.
By means of the purification step, both the product purity can be improved and impurities interfering in the further reaction, for example water or catalyst residues, can be separated off.
In a very particularly preferred embodiment, the reaction according to claim 1 is carried out in the presence of a sulfonic acid catalyst and the compound of the formula (1 ) obtained is subjected to a purification step.
The present invention also relates to a process for the preparation of optically pure (cis) and/or (trans)-sertraline or enantiomerically enriched mixtures of (cis)- and (trans)-sertraline. The process is characterized by the following reaction steps (I)-(III):
(I) reaction of pure sertralone of the formula (2) to give the sertraline of the formula (1) corresponding to the process according to claim 1,
(II) subsequent cis-selective hydrogenation with noble metal catalysts or other catalysts based on copper or nickel to give cis-sertraline-enriched mixtures of racemic cis- and trans-sertraline,
(III) subsequent mandelic acid-based resolution for the selective preparation of the desired enantiomerically pure cis isomer.
Starting from pure sertralone, sertraline is prepared according to the process described in claim 1. The imine is converted to cis-sertraline-enriched mixtures of racemic cis- and trans-sertraline in a subsequent cis-selective hydrogenation with noble metal catalysts or other catalysts based on copper or nickel on very different supports, such as, for example, carbon, alumina, silica, calcium carbonate, barium carbonate, barium sulfate etc.
In a subsequent mandelic acid-based resolution, the desired enantiomerically pure cis isomers can be crystallized.
The optically pure amine is liberated using sodium hydroxide solution and converted into the desired polymorphic form as the hydrochloride in suitable solvents.
The following examples illustrate the invention further. Details in parts or percentages relate to the weight.